Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade?

Abstract

Abnormal accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (LBs) is the neurpathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. These inclusions are mainly constituted of a presynaptic protein, α-synuclein (α-syn). Over the past decade, growing amounts of studies reported an aberrant accumulation of phosphorylated α-syn at the residue S129 (pS129) in the brain of patients suffering from PD, as well as in transgenic animal models of synucleinopathies. Whereas only a small fraction of α-syn (<4%) is phosphorylated in healthy brains, a dramatic accumulation of pS129 (>90%) has been observed within LBs, suggesting that this post-translational modification may play an important role in the regulation of α-syn aggregation, LBs formation and neuronal degeneration. However, whether phosphorylation at S129 suppresses or enhances α-syn aggregation and toxicity in vivo remains a subject of active debate. The answer to this question has important implications for understanding the role of phosphorylation in the pathogenesis of synucleinopathies and determining if targeting kinases or phosphatases could be a viable therapeutic strategy for the treatment of these devastating neurological disorders. In the present review, we explore recent findings from in vitro, cell-based assays and in vivo studies describing the potential implications of pS129 in the regulation of α-syn physiological functions, as well as its implication in synucleinopathies pathogenesis and diagnosis.

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

“…Finally, we investigated whether ambroxol was capable of lowering the levels of α‐synuclein phosphorylated at residue S129 and observed more than a 40% reduction in ambroxol‐treated SNCA/SNCA mice. This finding is particularly exciting in light of the growing recognition of the importance that phosphorylation of α‐synuclein plays in the pathogenesis of synucleinopathies 32. To our knowledge, this is the only study conducted to date that investigates the effect of ambroxol treatment on GCase activity and α‐synuclein in transgenic mice overexpressing human α‐synuclein in the absence of mouse α‐synuclein.…”

“…There is increasing evidence that phosphorylation of α‐synuclein may play a pivotal role in α‐synuclein aggregation and formation of Lewy bodies and neurites. Numerous studies reported excessive accumulation of α‐synuclein phosphorylated at residue S129 in the brain of PD patients, where phosphorylated α‐synuclein accounts for up to 90% of total α‐synuclein found within Lewy bodies 6, 32. Also, phosphorylation of α‐synuclein at residue S129 seems to be aberrantly accumulated in the brain of animal models of synucleinopathies 32…”

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease

“…The formation of PHFs requires hyperphosphorylated tau, and tau protein in neurofibrillary tangles is hyperphosphorylated, most notably at Ser 202 , Thr 231 and Thr 181 [41] . Interestingly, the alpha-synuclein that forms fibrils and is abundant in Lewy bodies in Parkinson's disease is also hyperphosphorylated, at a single serine site [42] .…”

“…Dimers of native FLNA, coupled to insulin receptors but not to α7nAChR or TLR4, are depicted as straight rods; red curly FLNA depicts the altered form, which is recruited to α7nAChR and TLR4 (and possibly also insulin receptors). Enabled by altered FLNA's new linkages, Aβ 42 activates α7nAChR to hyperphosphorylate tau and persistently activates TLR4 to induce inflammatory cytokine release (TNFα, IL-1β and IL-6) by reactive astrocytes. This neuroinflammation likely contributes to insulin receptor desensitization [57] .…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…Such immunogenic peptides mimic the C-terminus of α-syn [26], or can direct bind the oligomeric form of α-syn, or the Ser129 phosphorylated site of α-syn [27], which is a crucial site for α-syn accumulation [28].…”